TY - JOUR
T1 - Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression
AU - Du Bois, Philipp
AU - Tortola, Cristina Pablo
AU - Lodka, Doerte
AU - Kny, Melanie
AU - Schmidt, Franziska
AU - Song, Kunhua
AU - Schmidt, Sibylle
AU - Bassel-Duby, Rhonda
AU - Olson, Eric N.
AU - Fielitz, Jens
N1 - Publisher Copyright:
© 2015 American Heart Association, Inc.
PY - 2015/8/14
Y1 - 2015/8/14
N2 - Rationale: Skeletal muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure. The molecular mechanisms are imperfectly understood, although an activated renin-angiotensin aldosterone system has been implicated. Angiotensin (Ang) II induces skeletal muscle atrophy in part by increased muscle-enriched E3 ubiquitin ligase muscle RING-finger-1 (MuRF1) expression, which may involve protein kinase D1 (PKD1). Objective: To elucidate the molecular mechanism of Ang II-induced skeletal muscle wasting. Methods and Results: A cDNA expression screen identified the lysosomal hydrolase-coordinating transcription factor EB (TFEB) as novel regulator of the human MuRF1 promoter. TFEB played a key role in regulating Ang II-induced skeletal muscle atrophy by transcriptional control of MuRF1 via conserved E-box elements. Inhibiting TFEB with small interfering RNA prevented Ang II-induced MuRF1 expression and atrophy. The histone deacetylase-5 (HDAC5), which was directly bound to and colocalized with TFEB, inhibited TFEB-induced MuRF1 expression. The inhibition of TFEB by HDAC5 was reversed by PKD1, which was associated with HDAC5 and mediated its nuclear export. Mice lacking PKD1 in skeletal myocytes were resistant to Ang II-induced muscle wasting. Conclusion: We propose that elevated Ang II serum concentrations, as occur in patients with congestive heart failure, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting.
AB - Rationale: Skeletal muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure. The molecular mechanisms are imperfectly understood, although an activated renin-angiotensin aldosterone system has been implicated. Angiotensin (Ang) II induces skeletal muscle atrophy in part by increased muscle-enriched E3 ubiquitin ligase muscle RING-finger-1 (MuRF1) expression, which may involve protein kinase D1 (PKD1). Objective: To elucidate the molecular mechanism of Ang II-induced skeletal muscle wasting. Methods and Results: A cDNA expression screen identified the lysosomal hydrolase-coordinating transcription factor EB (TFEB) as novel regulator of the human MuRF1 promoter. TFEB played a key role in regulating Ang II-induced skeletal muscle atrophy by transcriptional control of MuRF1 via conserved E-box elements. Inhibiting TFEB with small interfering RNA prevented Ang II-induced MuRF1 expression and atrophy. The histone deacetylase-5 (HDAC5), which was directly bound to and colocalized with TFEB, inhibited TFEB-induced MuRF1 expression. The inhibition of TFEB by HDAC5 was reversed by PKD1, which was associated with HDAC5 and mediated its nuclear export. Mice lacking PKD1 in skeletal myocytes were resistant to Ang II-induced muscle wasting. Conclusion: We propose that elevated Ang II serum concentrations, as occur in patients with congestive heart failure, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting.
KW - angiotensin II
KW - gene expression regulation
KW - heart failure
KW - histone deacetylase 5
KW - muscle RING-finger-1
KW - protein kinase D
KW - transcription factor EB
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U2 - 10.1161/CIRCRESAHA.114.305393
DO - 10.1161/CIRCRESAHA.114.305393
M3 - Article
C2 - 26137861
AN - SCOPUS:84939533247
SN - 0009-7330
VL - 117
SP - 424
EP - 436
JO - Circulation research
JF - Circulation research
IS - 5
ER -